1. Area of the Art
The present invention is in the area of hematology and more specifically in the area of novel treatment for bleeding.
2. Description of the Background
The invention relates to improved compositions comprising red cell membrane-derived microparticles (RMP) that enhance blood coagulation, platelet activity, and promote blood clot formation and to a method for treating excessive bleeding including but not limited to those due to disorders of platelets and blood coagulation and to methods for manufacturing such compositions. The inventive compositions are useful in minimizing blood loss in a mammal, in particular in patients undergoing surgical or medical invasive procedures and those with trauma where blood loss can be substantial. RMP correct hemostatic abnormalities arising from blood clotting factor deficiencies, as well as from deficiency in platelet numbers (thrombocytopenia) and/or function (platelet dysfunction).
Excessive bleeding is among the most common of life-threatening complications in trauma and bleeding complications in both clinics and hospitals. The bleeding patient poses a major medical challenge in all medical specialties such as surgery, trauma, obstetrics/gynecology, cardiology, neurology, hematology, etc. At present, transfusion of banked blood products is the mainstay of treatment for excessive bleeding, but transfusion is very expensive [1] and carries risks of serious short- and long-term complications.
Timing is critical in bleeding patients. Prompt intervention is essential to patient management, but often many hours are required to type, cross-match, and deliver blood from the blood bank to the patient. Therefore, blood transfusion as presently employed often fails to save the lives of many bleeding victims. Furthermore, since blood products must often be given before the cause of bleeding is identified, transfusion may fail to arrest bleeding and merely replaces lost blood while the bleeding continues. Days or weeks of investigation may be required to find the underlying cause of excessive bleeding.
Treatments for bleeding differ depending on etiology of the bleeding. For example, (1) when excessive bleeding develops due to low platelet counts (thrombocytopenia) platelet transfusion or other measures to raise platelet counts must be used to arrest bleeding. In the case of impaired platelet function (dysfunction) treatment to improve platelet function or platelet transfusion are employed. (2) In the case of coagulation disorders, in which one or more of 13 clotting factors are low in level or are defective or inhibited, missing clotting factors must be supplied to arrest bleeding. In hemophilia A, factor VIII must be administered whereas in hemophilia B factor IX must be administered. Without these specific therapies to correct underlying etiology, bleeding will not stop and patients will be exposed to endless transfusions.
To save the lives of bleeding victims, we need agents that can be administered safely and immediately, at reasonable cost. An ideal product could be administered to patients on a moment's notice, regardless of the underlying etiology of the bleeding. No such agent is yet available in spite of a century-long search.
New and better products are urgently needed to promptly arrest bleeding in all situations regardless of the cause of bleeding. Such products will save many lives and will avoid needless transfusions and associated complications. Our RMP product meets all requirements of safety and efficacy required of a cost effective universal hemostatic agent. RMP can be infused at a moment's notice and is effective in the treatment of most bleeding conditions. It is also expected to be less costly and safer compared to other products intended for this purpose.
As already explained, blood can be a life-saving resource, but blood is becoming increasingly scarce and expensive due to rising demand, limited supply, and more stringent regulations. According to the National Blood Data Resource Center, 4.5 million people receive transfusion annually. The cost for red cell transfusions alone is $24 billion per year. This does not include platelets and other blood products. The hospital cost for transfusion-related adverse effects exceeds $10 billion per year [1]. Transfusions are associated with many short- and long-term complications including anaphylaxis, hemolytic reactions, transfusion induced immune suppression, graft-versus host disease, transfusion related acute lung injury (TRALI) and transmission of pathogens such as hepatitis, HIV and prion diseases (mad cow disease).
This situation can only get worse with increasing age of the population. For example, to prevent heart attacks, strokes and other thromboses that affect the elderly, increasing numbers of the patients are being treated with anticoagulants or antiplatelet therapy. The former includes Coumadin, Heparin, LMWH (low molecular weight Heparin), fondaparinux (Arixtra) and a new generation of oral thrombin or FXa inhibitors such a as dabigatran (Pradaxa) and rivaroxaban (Xarelto). The later include aspirin, Plavix (clopidogrel) and other antiplatelet drugs. All these new anticoagulants and antiplatelet medications have serious side effects of promoting bleeding and, thus, increase bleeding complication and, hence, the demand for more transfusions.
Some of the older drugs such as Coumadin and Heparin have antidotes. Therefore, bleeding from overdose of Coumadin can be treated with vitamin K, and Heparin can be neutralized by an antidote, such as protamine, to thereby limit bleeding. However, there is no effective antidote for new anticoagulants such as low molecular weight heparin, e.g., Lovenox (enoxaparin) (which can be partially reversed by protamine) and Fragmin (dalteparin), Arixtra (fondaparinux), Pradaxa (dabigatran) and Xarelto (rivaroxaban) and for most antiplatelet drugs (e.g., aspirin, Plavix and their analogs). Therefore, bleeding resulting from new anticoagulants and antiplatelet drugs imposes new challenges in patient management. At present, this bleeding is treated blindly with transfusion of blood/blood products. RMP administration can correct or improve coagulation abnormalities induced by both the new and older types of “blood thinners” as well as antiplatelet drugs as is shown in FIGS. 4A, 4B, 4C, 4D, 4E and 4H.
Although transfusion of banked blood is a mainstay of therapy for bleeding, other measures have been advocated, such as antifibrinolytic agents, DDAVP [2], but these treatments are not widely used because their efficacy is unproven. Recombinant Factor VIIa (i.e., NovoSeven) gained much attention and showed great promise [3], but its use is limited by prohibitive cost (e.g., in excess of $1 million for a single patient with high levels of FVIII inhibitors) and by reports of serious thrombotic complications. RMP has great potential for wide application in in various bleeding disorders and corrects hemostatic abnormalities induced by most anticoagulants including new generation anticoagulants as well as by most antiplatelet drugs. It can be stored in ambulances for use in emergency medicine (e.g., at accident sites) and in operating rooms, clinics, dental offices, pharmacies and hospitals, since it is stable at room temperature, is reasonable in cost and shows no sign of adverse effects.
Platelet MP (PMP) and lyophilized whole platelets (LyoPLT) [4] have also been proposed for treatment of bleeding. Lyophilized platelets (LyoPLT) are under current study but may be impractical compared to RMP due to (i) the high costs of scarce platelets, (ii) risk of thrombogenesis, and (iii) immuno-reactivity. The total volume of circulating platelets in blood is only 20 ml, about 1/250 that of red cells, so starting material is costly and scarce. Platelets are highly immunogenic due to HLA, ABO, Rh, and platelet-specific antigens, which are impractical to cross match, hence adverse reactions are frequent. Furthermore, platelets are known to carry tissue factor (TF) which is thrombogenic. In contrast, RMP have none of these disadvantages.